1. Fields of the invention
The present invention relates to a precursor used for labeling hepatocyte receptors, a method for preparing the same, a radiotracers for imaging, and a pharmaceutical composition of the same, especially to a bifuncitonal precursor containing trisaccharide and a diamide dimercaptide (N2S2) ligand, a method for preparing the same, a radiotracer, and a pharmaceutical composition of the same.
2. Descriptions of Related Art
Faced with an increasingly ageing and more competitive society, various kinds of diseases such as cancers, cerebrovascular diseases, diseases of nervous system and heart diseases seriously threaten our health. For early diagnosis, early treatment and prevention of these diseases, the development of functional and molecular techniques of diagnostic and treatment of the above diseases have become matters of great urgency.
In medical techniques available now, isotope tracer techniques and serum biochemical markers are commonly used for detecting human diseases or functional disorders. Both have advantages of safety, non-invasion, convenience and accuracy. As to the treatment target, the most popular applications are related to follow-up and treatment of liver diseases. Among liver diseases, liver fibrosis represents the liver's response to some simulates such as necrosis and inflammation and these stimulates arouse durative hyperplasia of fibril connective tissue in the liver. Liver fibrosis is reversible in early stage. The advanced liver fibrosis results in cirrhosis and cirrhosis is generally irreversible.
The main method for testing and diagnosis of liver fibrosis is liver puncture to get liver biopsy. The method has following shortcomings. Firstly, this is an invasive test method. Secondly, the method has the risk of complications including pain, bleeding, peritonitis, etc. The third, if the liver tissue obtained is too small or too short, there is an error in test results and clinical diagnosis. The fourth is that the test is with low reproducibility. The test is unable to be applied to patients on clinical repetitively for monitoring patient's conditions dynamically
According to international standard, liver fibrosis includes four stages. In the F1/F2(mild/moderate) stages, liver fibrosis is reversible and the treatment effect is optimal. The liver tissue can be back to normal state. In the F 3 stage (advanced fibrosis), the treatment effect is poor and liver fibrosis is severe. As to the stage F4, liver fibrosis is worsen to liver cirrhosis and is irreversible. Thus the earlier liver fibrosis is detected, the better the treatment effect of the patient.
Human cells have specific receptors on surfaces to accept some specific proteins or peptides. According to this specificity, some proteins or peptides are labeled with radioactive nuclides and are delivered into human bodies. Then the labeled proteins or peptides achieve higher concentration in specific organs or tissues so as to diagnose or treat diseases by using nuclear imaging.
In the past, bifunctional group ligand is used together with technetium compounds or rhenium compounds to label proteins or peptides. For example, compound S-Hynic with bifunctional group includes an active carboxylic acid that is used to form a strong amide bond with proteins or peptides. Moreover, it contains a pyridyl group and hydrazo structure that bond to 99mTc. While being used together with auxiliary chelating agents such as Tricine, S-Hynic reacts with technetium or rhenium to get stable complexes. However, S-Hynic solution is photosensitive and is not convenient in use. Thus there is a need to find out more stable organic compounds with bifunctional groups.
There are about two hundred thousand asialoglycoprotein receptors (ASGPR) on surfaces of mammalian heptocytes. The asialoglycoprotein receptor (ASGPR) is a liver-specific transmembrane glycoprotein that mediates endocytosis, removes desialylated glycoproteins, and involves in lipoprotein catabolism. The ASGPR also has high affinity to galactose (Gal) and N-acetylgalactosamine (GalNAc). Especially when a ground substance contains tri-Gals or N-acetylgalactosamine, it has higher affinity to ASGPR on surfaces of hepatocytes, almost 106 times than a substrate with a single N-acetylgalactosamine. Based on this characteristic, YEE (ah-GalNAc)3 has been used as a drug/gene carrier for drug or gene delivery to hepatocytes.
It is learned that carboxylic acids can bind to alcohols, saccharides(carbohydrates), amines, amino acids, peptides and proteins while diamide dimercaptide (N2S2) ligands bind to radioisotopes such as technetium or rhenium. But now there is no radioactive tracer for imaging of hepatocyte receptors formed by Gal, GalNAc and N2S2 ligand.
Both Gal and GalNAc have specificity to hepatic lectin. Once radioisotopes are connected to Gal and GalNAc of glycoprotein, nuclear pharmaceuticals are optimally delivered to the targeted liver cells and entered the cells by endocytosis for functional imaging or therapeutic use. The design of glycosyl group is not revealed yet in the field of nuclear medicine. Thus a preparation method for hepatocyte receptor labeled precursor containing trisaccharide and a diamide dimercaptide (N2S2) ligand is provided so as to increase sensitivity and specificity of nuclear medicine tests.